Purification of Indium 111

ABSTRACT

Undesirable metal cation contaminants, including cadmium, can be removed from a solution containing Indium-111, on a bed of an anion exchange resin. The thus purified solution can be stored and transported in a polypropylene vial, to prevent the possibility of cadmium entering the solution from a glassware wall and of Indium from being lost from the solution by chemically reacting with a glassware wall. The vial can be sealed with a rubber stopper which has a polytetrafluroethylene coating facing the solution to prevent the possibility of contaminants which could interfere with later uses of the Indium-111 from leaching into the solution from the rubber stopper. Recipients of the Indium-111-containing vial can be provided with a prepackaged column of the anion exchange resin to enable such recipients to remove the cadmium which accumulated in the solution as a product of radioactive decay during shipment.

BACKGROUND OF THE INVENTION

In one aspect, this invention relates to a chemical purificationprocess. In another aspect, the invention relates to a container forchemicals. In another aspect, the invention relates to a clean-up kitfor use with radioisotopes prior to the manufacture ofradiopharmiceutical products with such radioisotopes.

Indium-111 is a radioisotope which is used for radio-diagnostic andradio-therapeutic purposes. Indium-111 (atomic number 49) has ahalf-life of about 2.8 days and decays by emission of an electron toform cadmium-111 (atomic number 48). The short half-life is beneficialfrom the standpoint of quickly breaking down when administered to apatient, but is problematic from the standpoint of requiring extremelyprompt (and careful) handling of the material between the producer ofthe radioisotope and the patient. Delays between the time of productionof the material its incorporation into a pharmaceutical material, andits administration to a patient result in a decrease in the amount ofIndium-111, with a resultant decrease in radioactive potency(curies/volume), and a concomitant increase in the concentration of thecadmium decay product (mass/volume).

Indium-111 is typically received for the preparation of aradiopharmaceutical in a small glass vial which contains a specific doseof Indium-111 chloride in hydrochloric (HCl) acid solution. The dose istypically measured by the radioactive output of the vial, typically inmillicuries. The radioactive output is typically a calculated value fora specific time and day. In order to deliver the calculated dose to atarget site, it is necessary to transfer all of the Indium-111 in thevial to the target site at the indicated time.

Delivery is typically accomplished by incorporating the Indium-111 intoa radiopharmaceutical product. This is typically done by reacting theIndium-111 with an organic moiety, such as a peptide, which will seekthe target site when introduced into the patient. The stoichiometries ofthe reactions between the Indium-111 and the organic moiety, and theradiopharmaceutical and the target site, however, is complicated by thepresence of the cadmium, and may be further complicated by the presenceof further impurities commonly found in Indium-111 solution, such asiron, lead, zinc, aluminum and copper.

The cadmium competes with the Indium-111 for reaction with the organicmoiety, and the cadmium-pharmaceutical competes with the Indium-111radiopharmaceutical for binding with the target site. Stoichiometry isalso complicated by the fact that a significant portion of theindium-111 cannot be easily removed from the vial. Apparently, a portionof the indium can become chemically bound to the glass. Further, theamount of cadmium which is present can be greater than the amountcalculated as being present from the decay of the Indium-111 .Apparently, cadmium, as well as other impurities which are inherent tothe glass, can be leached out by the solution from the inside of theglass vial.

The glass wall of the vial causes a further complication in delivering aprescribed radioactive dose to the target site. The actual output of theradioactive material in the vial is often different from the measuredradioactive output from the vial, due to attenuation or radioactiveshielding by the glass wall of the vial, and can be as much as 30%higher.

Simple techniques for removing the cadmium from the Indium-111 solutionand for getting all of the Indium-111 from the vial would be verydesirable, as this would enable higher quantities of ultra-pureIndium-111 to be delivered to the target site.

Techniques for providing ultra-pure Indium-111 to the end user, and forenabling the end user to better assess the potency of the dose ofIndium-111 to be administered would also be desirable.

SUMMARY OF THE INVENTION

It has been found that undesirable metal cation contaminants, includingcadmium, can be removed from a solution containing Indium-111, on a bedof an anion exchange resin.

It has been further found that a polypropylene vial containing a sterilesolution of Indium-111 chloride in dilute HCl is easily emptied ofIndium-111 as the solution does not adhere to the plastic wall of thevial. The solution furthermore does not pick up environmental cadmiumfrom the vial, or other metals, since these materials are not foundpolypropylene.

With a glass vial, as much as 20% of the Indium-111 remains behind whenthe vial is emptied. With a polypropylene vial, more than 99% of theIndium-111 is easily emptied from the vial. With a glass vial, themeasured radioactivity of the vial is up to 30% less than the actualradioactivity of the Indium-111 in the vial. With a polypropylene vial,the measured activity through the wall of the vial is much closer toactual levels. The use of a polypropylene vial thus results in lesswaste of Indium-111, a more pure form of Indium-111, and a more easilymeasured amount of Indium-111.

It has been further found that providing a rubber stopper to seal thevial which has a polytetrafluroethylene coating facing the solution willprevent contaminants which could interfere with the stoichiometriesmentioned previously from leaching from the rubber and into thesolution. The stopper is preferably formed from vinyl butyl rubber andthe coating is preferably Teflon® brand polytetrafluoroethylene.

It is further proposed to provide a column containing a strong anionexchange resin to recipients of an HCl solution of Indium-111, to enablesuch recipients, prior to further use of the solution, to remove thecadmium which accumulated, due to radioactive decay of the Indium-111,in the solution during shipment.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross-sectional view illustrating certain features of a vialaccording to one embodiment of the invention.

FIG. 2 is a pictorial view illustrating certain features of a kitincluding a column, a filter, and a vial according to another embodimentof the invention.

FIG. 3 is a cross sectional view of a stopper well adapted for use withthe vial shown in FIG. 2.

FIG. 4 is a cross sectional view of a radiation protection shield inaccordance with certain aspects of the invention containing a kitsimilar to that shown in FIG. 2 in dashed lines.

DETAILED DESCRIPTION OF THE INVENTION

One embodiment of the invention provides a process for purifying asolution of Indium-111 which contains undesirable metal cationcontaminants. The process is carried out by contacting the solution witha bed of an anion exchange resin under conditions that retain theundesirable metal cation contaminants on the bed.

The process is effective to remove cadmium from the solution, as well ascertain other metal contaminants such as zinc and/or iron. The solutionsusceptible to treatment in accordance with this aspect of the inventionis generally a dilute solution of a strong acid, usually HCl. The bed ofresin which is employed in this aspect of the invention is mostpreferably contained in the form of a strong anion exchange resin in acolumn and the contacting occurs by flowing the solution through thecolumn. The most preferred resin comprises a strongly basic anionexchange resin which is about 8% cross linked.

Good results have been obtained where the column has been prepped byfirst flowing an HCl solution through the column to form an HCl-treatedcolumn, then flowing an NaCl solution through the HCl treated column toform an NaCl treated column, and then flowing sterile water through theNaCl-treated column. These preparative steps assist in eluting asterile, nonpyrogenic product.

The anion exchange resin is preferably in a powdered form, generallycomprising particles having a particle size predominantly in the rangeof about to 100 to about 200 mesh. To speed solution flow though thecolumn, it is preferred to employ a sterile gas pressure enhanced headon the column. This can be carried out by injecting a sterile gas intoan upper end of the column to push the solution of Indium 111 throughthe column.

With reference to FIG. 1, there is provided in accordance with certainaspects of the invention a polypropylene vial 2 containing a sterilesolution 4 of Indium-111 chloride in dilute HCl solution. Generallyspeaking, the vial will contain in the range of from about 0.1 to about1000 mCi, usually from about 1 to about 500 mCi, of Indium-111 andessentially no cadmium. The volume of the solution will generally rangefrom about 0.05 ml to about 50 ml, usually in the range of from about0.1 to about 10 ml. The pH will generally range from about 0.1 to about2.0, usually in the range of from about 0.5 to about 1.5.

Preferably, a rubber stopper 6 seals the vial 2. The rubber stopper 6preferably forms a pierceable septum and has a polytetrafluroethylenecoating 8 facing the solution 4. A metal band 10, generally formed fromaluminum, positions the stopper in reliable sealing engagement with thevial.

Generally speaking, the container portion of the invention shown in FIG.1 is known. It is the use of a container of this type to contain thejust described solution of Indium-111 which constitutes this aspect ofthe invention.

FIG. 2 illustrates a column system 12 for removing cadmium from an HClsolution of Indium-111. The column system 12 comprises a column 14having an upper end 16 and a lower end 18. The lower end defines acolumn outlet. The upper end is generally sealed by a pierceable septum17. The column preferably tapers from the upper end to the lower end. Abed 20 of a powdered strong anion exchange resin, which can be aspreviously described, is positioned in the column 14. The bed ispositioned so as to define a gas head space 22 in the upper end of thecolumn beneath the septum 17. A support means 24 for supporting the bedis positioned inside of the column near the lower end thereof Adisk-shaped frit forms a suitable support means 24.

The system preferably further comprises a filter means 26 having anupper inlet 28 and a lower outlet 30. The upper inlet 28 is sealinglyengageable with the column outlet 18. The filter preferably removes anyparticles greater than 0.2 microns in size and assures productsterility. A first annular flange 32 is preferably positioned on anouter surface of the column near the lower end thereof A second annularflange 34 is preferably positioned on an outer surface of the filternear the upper inlet end thereof The flanges facilitate attaching theirrespective items to support apparatus and to each other.

FIG. 4 illustrates in cross sectional view a radiation protection shieldsystem 50 containing a column system 12' similar to that describedabove. To provide adequate shielding for Indium-111, it is preferredthat the wall thickness of at least those portions of the shield betweenthe fluid in the column system and the user constitute at least one inchof lead. The system 50 as shown is generally cylindrical in shape, andhas a bottom end closure 52 and a top end closure 54. Preferably, thesystem 50 comprises a lower portion 56 which forms a receptacle forreceiving the vial, a tubular extension 58 mounted on an upper end ofthe lower portion 50 to shield the column, and an upper portion 60 whichprovides a top streaming shield. The portions of the shield system canbe provided with alignment guides such as a tongue and groove structure62 as illustrated in FIG. 4 to provide additional structural stabilityand to eliminate a potential radiation leakage path if desired.

The items shown in FIGS. 1-4 provide a kit which can be used by an enduser to remove cadmium which has accumulated in a solution of Indium-111as a product of radioactive decay. The kit would preferably be usedimmediately prior to utilizing the solution in the preparation and/orlabeling of an Indium-111 based radiopharmaceutical. The kit comprises avial, a column, a filter, a polypropylene receptacle, and a stopper. Asused, the kit preferably further comprises a radioactive shield and asterile air supply.

A suitable vial is exemplified by the sealed vial 2 as shown in FIG. 1.The vial 2 contains a sterile HCl solution 4 of Indium-111.

A suitable column is exemplified by is the column 14 as shown in FIG. 2.The column 14 contains a bed of a powdered strong anion exchange resinto remove the cadmium from the solution upon passage of the solutionthrough the column.

A suitable filter is exemplified by the filter 26 as shown in FIG. 2.The filter 26 removes small particles from the solution after passage ofthe solution through the bed of powdered strong anion exchange resin andassures sterility.

A suitable polypropylene receptacle exemplified by the sterilepolypropylene vial 36 shown in FIG. 2. The vial receives the solutionafter passage through the filter and has a volume sufficient toaccommodate the filtered solution.

A suitable stopper is exemplified by the stopper 38 shown in FIG. 3.This stopper is for sealing the vial 36 of filtered solution, after theremoval of the filter 26 and the column 14. The stopper 38 has apolytetrafluroethylene coating 40 and seals the vial.

Certain aspects of the invention are further illustrated by thefollowing example.

EXAMPLE

General

Because cadmium is a ubiquitous environmental contaminant, great caremust be taken to insure that the environment including the reagents,column with anion exchange resin, and process equipment such asglassware, if used, and plasticware be essentially cadmium-free. It ispreferred to avoid glassware.

Extremely pure water and acids having a cadmium content of well below 1ppb should be used. The laboratory should be a non-smoking area, sincecigarette smoke contains cadmium. Handling should be carried out in asterile flow hood. Glassware, if used, should be acid washed andplasticware, preferably polypropylene, should be metal free. Glovesshould be used in handling the equipment and test tubes and containersshould be kept covered to prevent airborne contamination.

Analysis for cadmium may be done by atomic absorption technique and ispreferably carried out by electrothermal atomic absorptionspectrophotometry (ETAAS). The principle of this technique is based uponthe absorption of light at element-specific wavelengths (resonance line)for neutral atoms in the ground state. Solutions suspected of containingcadmium are placed onto a piece of pyrolytically coated graphite anddried. The graphite is heated very quickly by passing an electricalcurrent across it. When the temperature of the graphite reaches theboiling point of the element (or salt), the element forms a gaseouscloud in the light path. The amount of light that is absorbed isproportional to the quantity of ground state neutral atoms formed fromthe element deposited on the graphite. Preferred ETAAS equipment isprovided with a deuterium background correction.

The following information describes the process by which In-111 chlorideis purified.

Step 1: Receipt of bulk In-111 chloride solution from radionuclideproduction facility

The bulk In-111 chloride solution is received from the supplier 48 hourspost-irradiation of a Cd-112 target The solution consists of the In-111chloride in a solution of 0.05 N HCl. Specifications from the producerof this radionuclide include the following:

    ______________________________________                                        Cu.sup.2+  <2 ng/mCi   Pb.sup.2+ <2 ng/mCi                                      Fe.sup.3+ <2 ng/mCi Zn.sup.2+ <2 ng/mCi                                       Cd.sup.2+ <2 ng/mCi Ni.sup.2+ <2 ng/mCi                                     ______________________________________                                    

Exemplary metal levels which have been actually measured in the startingmaterial are

Cd²⁺ : 2.002 ng/mCi, Cu²⁺ : 0.661 ng/mCi, and Pb²⁺ : 0.743 ng/mCi.

Step 2: Purification of bulk In-111 chloride solution

Purification of the bulk In-111 chloride solution is performed usingcolumn chromatography with a strong anion exchange resin. The stronganion exchange resin was purchased from Aldrich, catalog #21742-5, Dowex1X8-200 ion exchange resin (Dowex-1-chloride, strongly basic anion. 8%crossing, 100-200 dry mesh).

A. The column is prepared by adding 1.5 Gm of the anion exchange resinto the Biorad column (731-1550). Next, 10 mL of 0.1 N HCl is elutedthrough the column. After the addition of the 0.1 N HCl, 10 ml of 0.9%NaCl for injection is eluted through the column. Finally, 10 mL ofsterile water for injection is eluted through the column.

B. The column is blown dry and then the entire volume of the bulk In-111chloride solution is applied to the top of the column resin. Thesolution is passed through the column by application of a stream of airthrough a sterile syringe attached to the top of the column. The elutedpurified solution is collected through a 0.2 μ filter and into a 10-mLsterile polypropylene plastic vial. If more than 20% of the initialradioactivity remains on the column after elution, the column is rinsedwith approximately 0.5 ml 0.05 N HCl through the same 0.2 μ filter. Bothelutions are then pooled into the same sterile polypropylene plasticvial and assayed.

Step 3: Test to determine cadmium content

A. A 10 μL sample is withdrawn from the sterile plastic vial (Step 2B)and diluted with 1990 μL of 1% nitric acid to yield a 1:200 dilution ina volume of 2 mL.

B. The diluted solution is analyzed for cadmium using an atomicabsorption graphite furnace.

Step 4: Target specifications

The product from Step 2 is a sterile, pyrogen-free radiochemicalsolution presently approved for investigational use only. The activeingredient is In-111 chloride in 0.05 N (+/-0.01 N) HCl (pH 1.0),typically shipped 0.5 ml per vial, specific activity 26.0 mCi/ml, totalactivity 13.0 mCi. Radionuclide purity is 99.9% (min.) In-111, others0.1% (max.). Chemical purity is

    ______________________________________                                        Cu.sup.2+ <2 ng/mCi    Pb.sup.2+ <2 ng/mCi                                      Fe.sup.3+ <2 ng/mCi Zn.sup.2+ <2 ng/mCi                                       Cd.sup.2+ essentially 0 Ni.sup.2+ <2 ng/mCi                                 ______________________________________                                    

Exemplary metal levels which have actually been measured in the productare:

    ______________________________________                                        0.377 ng/mCi Cu.sup.2+ ;                                                                    0.181 ng/mCi Pb.sup.2+ ;                                                                    <2 ng/mCi Fe.sup.3+ ;                               <2 ng/mCi Zn.sup.2+ ; 0.045 ng/mCi Cd.sup.2+ ; <2 ng/mCi Ni.sup.2+.         ______________________________________                                    

While certain preferred embodiments of the invention have been describedherein, the invention is not to be construed as being so limited, exceptto the extent that such limitations are found in the claims.

What is claimed is:
 1. A processfor purifying a dilute HCl solution ofIndium-111 which contains undesirable cadmium cation contaminant, saidprocess comprising contacting said solution with a bed of an anionexchange resin under conditions to retain the cadmium cation contaminantin the bed, wherein the bed of resin forms a strong anion exchangeinside a column and the contacting occurs by flowing the solutionthrough the column, and the column is prepared for purifying thesolution of Indium-111 by flowing an HCl solution through the column toform an HCl treated column and then flowing an NaCl solution through theHCl treated column to form an NaCl treated column.
 2. A process as inclaim 1 further comprising further preparing the column for purifyingthe solution of Indium-111 by flowing sterile water through theNaCl-treated column.
 3. A process as in claim 2 wherein the column hasan upper end and a lower end, said process further comprising injectinga gas into an upper end of the column to push the solution of Indium 111through the column.
 4. A process as in claim 3 wherein the anionexchange resin is in powdered form.
 5. A process as in claim 4 whereinthe anion exchange resin comprises particles having a particle sizepredominantly in the range of about to 100 to about 200 mesh.
 6. Aprocess as in claim 5 wherein the anion exchange resin is strongly basicanion, 8% cross linking.